2. Academic Validation
  3. A distinct structural mechanism underlies TRPV1 activation by piperine

A distinct structural mechanism underlies TRPV1 activation by piperine

  • Biochem Biophys Res Commun. 2019 Aug 20;516(2):365-372. doi: 10.1016/j.bbrc.2019.06.039.
Yawen Dong 1,  Yue Yin 1,  Simon Vu 2,  Fan Yang 3,  Vladimir Yarov-Yarovoy 2,  Yuhua Tian 4,  Jie Zheng 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, Shandong, China.
  • 2 Department of Physiology and Membrane Biology, UC Davis School of Medicine, Davis, CA, 95616, USA.
  • 3 Department of Biophysics and Kidney Disease Center, First Affiliated Hospital, Institute of Neuroscience, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
  • 4 Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, Shandong, China. Electronic address: yhtian05250@qdu.edu.cn.
  • 5 Department of Physiology and Membrane Biology, UC Davis School of Medicine, Davis, CA, 95616, USA. Electronic address: jzheng@ucdavis.edu.
PMID: 31213294 DOI: 10.1016/j.bbrc.2019.06.039
Abstract

Piperine, the principle pungent compound in black peppers, is known to activate the capsaicin receptor TRPV1 ion channel. How piperine interacts with the channel protein, however, remains unclear. Here we show that piperine binds to the same ligand-binding pocket as capsaicin but in different poses. There was no detectable detrimental effect when T551 and E571, two major sites known to form hydrogen bond with capsaicin, were mutated to a hydrophobic amino acid. Computational structural modeling suggested that piperine makes interactions with multiple Amino acids within the ligand binding pocket, including T671 on the pore-forming S6 segment. Mutations of this residue could substantially reduce or even eliminate piperine-induced activation, confirming that T671 is an important site. Our results suggest that the bound piperine may directly interact with the pore-forming S6 segment to induce channel opening. These findings help to explain why piperine is a weak agonist, and may guide future efforts to develop novel pharmaceutical reagents targeting TRPV1.

Keywords

Agonist; CPZ; Capsaicin; ECS; Nociception; Pepper; Pungency; Spice; TRPA1; The abbreviations used are; VDW; capsazepine; extracellular solution; mTRPV1; mouse transient receptor potential cation channel, subfamily V, member 1; transient receptor potential cation channel, subfamily A, member 1; van der Waals.

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